Polymorphic forms of naltrexone

ABSTRACT

This invention relates to the discovery of novel polymorphic forms of naltrexone, including solvates, hydrates, anhydrous and other crystalline forms and combinations thereof. These novel forms of naltrexone impart advantages in pharmaceutical formulations incorporating them, including sustained release, or long acting, formulations.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/794,365, filed Oct. 26, 2017 which is a continuation of U.S.application Ser. No. 15/381,581, filed Dec. 16, 2016, now U.S. Pat. No.9,827,240, issued Nov. 28, 2017, which is a continuation of U.S.application Ser. No. 15/175,399, filed Jun. 7, 2016, now U.S. Pat. No.9,556,189, issued Jan. 31, 2017, which is a continuation of U.S.application Ser. No. 14/945,607, filed Nov. 19, 2015, now U.S. Pat. No.9,365,580, issued Jun. 14, 2016, which is a continuation of U.S.application Ser. No. 14/612,904, filed Feb. 3, 2015, now U.S. Pat. No.9,221,830, issued Dec. 29, 2015, which is a continuation of U.S.application Ser. No. 14/249,613, filed Apr. 10, 2014, now U.S. Pat. No.8,975,272, issued Mar. 10, 2015, which is a continuation of U.S.application Ser. No. 13/690,327, filed Nov. 30, 2012, now U.S. Pat. No.8,735,420, issued May 27, 2014, which is a continuation of U.S.application Ser. No. 11/860,677, filed Sep. 25, 2007, now U.S. Pat. No.8,389,540, issued Mar. 5, 2013, which is a divisional of U.S.application Ser. No. 10/860,608, filed Jun. 3, 2004, now U.S. Pat. No.7,279,579, issued Oct. 9, 2007, which claims the benefit of U.S.Provisional Application No. 60/475,863 filed on Jun. 4, 2003. The entireteachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Alcohol dependence is a prevalent disease with substantial morbidity andmortality. Detoxification and psychosocial therapy provide the basis oftreatment; in addition, pharmacotherapy is becoming widely accepted.Administered orally, naltrexone, a potent opioid antagonist, has beenshown to reduce relapse to heavy drinking in alcohol dependent patients,decrease the number of drinks consumed when relapse does occur, andpromote abstinence. Naltrexone has been reported to reduce both cravingand the reinforcing euphoric qualities of alcohol.

Although naltrexone has been shown to be effective as a maintenanceagent in the treatment of alcohol dependence, a major limitation of itsutility can be poor adherence to therapy. In the treatment of alcoholabuse, oral naltrexone must be taken on a daily basis. In a clinicaltrial comparing oral naltrexone to placebo, greater than 40% of patientstreated with naltrexone were noncompliant with the daily oral regimen.In medication-noncompliant patients relapse to clinically significantdrinking was similar to placebo treated patients and significantlyhigher than the rate observed with medication-compliant patients.

Polymorphs, solvates and salts of various drugs have been described inthe literature as imparting novel properties upon the drug. Thesepolymorphs can have different solubilities, stabilities and processingcharacteristics, presenting opportunities and challenges.

SUMMARY OF THE INVENTION

This invention relates to the discovery of novel amorphous andpolymorphic forms of naltrexone, including solvates, solvatomorphs,hydrates, anhydrous and other crystalline forms and combinationsthereof. These novel forms of naltrexone impart advantages inpharmaceutical formulations incorporating them, including sustainedrelease, or long acting, formulations. The solvates, or solvatomorphs,can include stoichiometric and non-stoichiometric solvates, such asclathrates, for example.

The present invention provides polymorphic forms of naltrexone which arecharacterized by X-ray Powder Diffraction (XRPD), differential scanningcalorimetry (DSC) or attenuated total reflectance infrared absorptionspectroscopy (IR-ATR).

The present invention advantageously provides novel polymorphic forms ofnaltrexone comprising naltrexone ethanolate, anhydrous naltrexone,naltrexone monohydrate, benzyl alcohol solvate and other polymorphs ofnaltrexone either isolated or in combination.

In another aspect, the invention, provides methods of making novelpolymorphic forms of naltrexone comprising (i) mixing a naltrexone, suchas a naltrexone base anhydrous and/or hydrochloride or other salt, witha solvent selected from the group consisting of acetonitrile, dimethylformamide, water, methanol, ethanol, benzyl alcohol, dichloromethane,acetone, ethyl acetate, methyl ethyl ketone, toluene and hexane; (ii)heating the mixture to within 1-10° C. of the boiling point to prepare anearly saturated solution; (iii) cooling the resulting nearly saturatedsolution to room temperature forming precipitated material; and (iv)harvesting the precipitated material.

A further aspect of the invention provides pharmaceutical compositionscontaining the naltrexone forms disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated, but in no way limited, by the Tablesherein and the following examples, with reference to the figures inwhich:

FIG. 1A is a graph depicting the X-ray Powder Diffraction (XRPD)patterns of crystalline naltrexone formed by slow cooling fromacetonitrile (dipolar aprotic).

FIG. 1B is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using acetonitrile(dipolar aprotic).

FIG. 2A is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by slow cooling using dimethyl formamide(dipolar aprotic).

FIG. 2B is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using dimethyl formamide(dipolar aprotic).

FIG. 3 is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using water (protic).

FIG. 4A is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by slow cooling using methanol (protic).

FIG. 4B is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using methanol (protic).

FIG. 5A is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by slow cooling using ethanol (protic).

FIG. 5B is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using ethanol (protic).

FIG. 6 is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using benzyl alcohol(protic).

FIG. 7A is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by slow cooling using dichloromethane(Lewis acidic).

FIG. 7B is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using dichloromethane(Lewis acidic).

FIG. 8A is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by slow cooling using acetone (Lewisbasic).

FIG. 8B is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using acetone (Lewisbasic).

FIG. 9A is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by slow cooling using ethyl acetate (Lewisbasic).

FIG. 9B is a graph depicting X-ray Powder Diffraction (XRPD) patterns ofcrystalline naltrexone formed by fast cooling using ethyl acetate (Lewisbasic).

FIG. 10A is a graph depicting X-ray Powder Diffraction (XRPD) patternsof crystalline naltrexone formed by slow cooling using methyl ethylketone (Lewis basic).

FIG. 10B is a graph depicting X-ray Powder Diffraction (XRPD) patternsof crystalline naltrexone formed by fast cooling using methyl ethylketone (Lewis basic).

FIG. 11A is a graph depicting X-ray Powder Diffraction (XRPD) patternsof crystalline naltrexone formed by slow cooling using toluene(aromatic).

FIG. 11B is a graph depicting X-ray Powder Diffraction (XRPD) patternsof crystalline naltrexone formed by fast cooling using toluene(aromatic).

FIG. 12A is a graph depicting X-ray Powder Diffraction (XRPD) patternsof crystalline naltrexone formed by slow cooling using hexane(non-polar).

FIG. 12B is a graph depicting X-ray Powder Diffraction (XRPD) patternsof crystalline naltrexone formed by fast cooling using hexane(non-polar).

FIG. 13A is a graph depicting a DSC of crystalline naltrexone formed byslow cooling using acetonitrile (dipolar aprotic).

FIG. 13B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using acetonitrile (dipolar aprotic).

FIG. 14A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using dimethyl formamide (dipolar aprotic).

FIG. 14B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using dimethyl formamide (dipolar aprotic).

FIG. 15 is a graph depicting DSC of crystalline naltrexone formed byfast cooling using water (protic).

FIG. 16A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using methanol (protic).

FIG. 16B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using methanol (protic).

FIG. 17A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using ethanol (protic).

FIG. 17B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using ethanol (protic).

FIG. 18 is a graph depicting DSC of crystalline naltrexone formed byfast cooling using benzyl alcohol (protic).

FIG. 19A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using dichloromethane (Lewis acidic).

FIG. 19B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using dichloromethane (Lewis acidic).

FIG. 20A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using acetone (Lewis basic).

FIG. 20B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using acetone (Lewis basic).

FIG. 21A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using ethyl acetate (Lewis basic).

FIG. 21B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using ethyl acetate (Lewis basic).

FIG. 22A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using methyl ethyl ketone (Lewis basic).

FIG. 22B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using methyl ethyl ketone (Lewis basic).

FIG. 23A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using toluene (aromatic).

FIG. 23B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using toluene (aromatic).

FIG. 24A is a graph depicting DSC of crystalline naltrexone formed byslow cooling using hexane (non-polar).

FIG. 24B is a graph depicting DSC of crystalline naltrexone formed byfast cooling using hexane (non-polar).

FIG. 25A is a graph depicting IR-ATR of crystalline naltrexone formed byslow cooling using acetonitrile (dipolar aprotic).

FIG. 25B is a graph depicting IR-ATR of crystalline naltrexone formed byfast cooling using acetonitrile (dipolar aprotic).

FIG. 26A is a graph depicting IR-ATR of crystalline naltrexone formed byslow cooling using dimethyl formamide (dipolar aprotic).

FIG. 26B is a graph depicting IR-ATR of crystalline naltrexone formed byfast cooling using dimethyl formamide (dipolar aprotic).

FIG. 27 is a graph depicting IR-ATR of crystalline naltrexone formed byfast cooling using water (protic).

FIG. 28A is an IR-ATR of crystalline naltrexone formed by slow coolingusing methanol (protic).

FIG. 28B is an IR-ATR of crystalline naltrexone formed by fast coolingusing methanol (protic).

FIG. 29A is an IR-ATR of crystalline naltrexone formed by slow coolingusing ethanol (protic).

FIG. 29B is an IR-ATR of crystalline naltrexone formed by fast coolingusing ethanol (protic).

FIG. 30 is an IR-ATR of crystalline naltrexone formed by fast coolingusing benzyl alcohol (protic).

FIG. 31A is an IR-ATR of crystalline naltrexone formed by slow coolingusing dichloromethane (Lewis acidic).

FIG. 31B is an IR-ATR of crystalline naltrexone formed by fast coolingusing dichloromethane (Lewis acidic).

FIG. 32A is an IR-ATR of crystalline naltrexone formed by slow coolingusing acetone (Lewis basic).

FIG. 32B is an IR-ATR of crystalline naltrexone formed by fast coolingusing acetone (Lewis basic).

FIG. 33A is an IR-ATR of crystalline naltrexone formed by slow coolingusing ethyl acetate (Lewis basic).

FIG. 33B is an IR-ATR of crystalline naltrexone formed by fast coolingusing ethyl acetate (Lewis basic).

FIG. 34A is an IR-ATR of crystalline naltrexone formed by slow coolingusing methyl ethyl ketone (Lewis basic).

FIG. 34B is an IR-ATR of crystalline naltrexone formed by fast coolingusing methyl ethyl ketone (Lewis basic).

FIG. 35A is an IR-ATR of crystalline naltrexone formed by slow coolingusing toluene (aromatic).

FIG. 35B is an IR-ATR of crystalline naltrexone formed by fast coolingusing toluene (aromatic).

FIG. 36A is an IR-ATR of crystalline naltrexone formed by slow coolingusing hexane (non-polar).

FIG. 36B is an IR-ATR of crystalline naltrexone formed by fast coolingusing hexane (non-polar).

FIG. 37 is the DSC of an ethanolate (clathrate) form of naltrexone.

FIG. 38 is a graph showing a 2-Theta scale crystallinity of analtrexone-containing microparticle composition of the instant inventionas a function of process steps.

FIG. 39 is an XRPD in 2-Theta scale of a representative composition ofthe instant invention.

FIG. 40 is a bar graph representing the mean polymorph distribution asreported in Table 5A.

FIG. 41A is a graph representing the effect of the percentage ofcrystallinity of a composition of the instant invention on its in vitrodrug release.

FIG. 41B is a graph representing the effect of the percentage ofcrystallinity of a composition of the instant invention on its in vivodrug release.

FIG. 42 is a DSC of amorphous naltrexone.

FIG. 43 is an XRPD pattern for naltrexone base anhydrous.

FIG. 44 is an XRPD pattern for naltrexone monohydrate.

FIG. 45 is an XRPD pattern for naltrexone benzyl alcohol solvate.

FIG. 46 is an XRPD pattern for naltrexone ethanolate.

FIG. 47 is a graph illustrating the effect of crystallinity onmicroparticle impurity generation at controlled room temperature.

FIG. 48 is a graph illustrating the effect of crystallinity onmicroparticle decay at controlled room temperature.

FIGS. 49A and 49B illustrate the effect of crystallinity on in vitro andin vivo drug release.

DETAILED DESCRIPTION OF THE INVENTION

In the course of research, Applicants surprisingly discovered novelnaltrexone polymorphs, including solvates, hydrates and anhydrous formsand combinations thereof. Further investigation led to the realizationthat favorable properties in naltrexone-containing microparticles weredue to the crystalline forms and non-crystalline forms of the naltrexonecontained within the microparticles. Applicants appreciated that thepolymorphic forms of naltrexone crystalline, for example, the ethanolsolvate form of naltrexone, have good to superior properties innaltrexone-containing compositions.

Pharmaceutical compositions when formulated for administration areuseful in the treatment and prevention of, for example, narcotic oralcohol addiction and autism, as well as other naltrexone-basedtherapies.

As with all pharmaceutical compounds and compositions, the chemical andphysical properties of the naltrexone form(s) utilized can be importantin its commercial development. These properties include, but are notlimited to: (1) packing properties such as molar volume, density andhygroscopicity, (2) thermodynamic properties such as meltingtemperature, vapor pressure and solubility, (3) kinetic properties suchas dissolution rate and stability (including stability at ambientconditions, especially to moisture, and under storage conditions), (4)surface properties such as surface area, wettability, interfacialtension and shape, (5) mechanical properties such as hardness, tensilestrength, compactibility, handling, flow and blend; and (6) filtrationproperties. These properties can affect, for example, processing andstorage of pharmaceutical compositions comprising naltrexone. Solidstate forms of naltrexone that provide an improvement in one or more ofthese properties relative to other solid state forms of naltrexone aredesirable.

The polymorphs of the invention and the compositions containing themhave the advantage that they are in a form which provides for improvedease of handling. Further, depending upon the intended use, they haveimproved chemical and solid state stability. For example, they may bestable when stored over prolonged periods of time. They may be preparedin good yields, in higher purity, in less time, more conveniently and ata lower cost, than forms of naltrexone prepared previously.

1 Crystallization of Naltrexone in a Variety of Solvents

A series of naltrexone samples were generated by the crystallization ofbulk drug substance at different rates out of a variety of solvents.These materials have been characterized by x-ray powder diffraction(XRPD), differential scanning calorimetry (DSC), and attenuated totalreflectance infrared absorption spectroscopy (IR-ATR).

The isolated crystal form of a substance often is a function of thenature of the crystallization solvent and of the rate it is crystallizedout of that solvent. The solvents in the following list includerepresentatives from all solvent classes, and crystallization out ofthese enable unique crystal forms accessible to naltrexone.

TABLE 1 Solvent System Type Preferred Solvents Dipolar aproticAcetonitrile, Dimethyl formamide Protic Water, Methanol, Ethanol, Benzylalcohol Lewis acidic Dichloromethane Lewis basic Acetone, Ethyl acetate,Methyl ethyl ketone Aromatic Toluene Non-polar Hexane

2. Methods for Identifying the Novel Forms

Applicants prepared substantially pure polymorphic forms of naltrexoneusing two separate processes. In one process, Applicant prepared thecrystalline naltrexone polymorphs using a slow cooling process (“slow”).Commercially available naltrexone base anhydrous (Mallinckrodt) wasdissolved in solvent forming a solvent system. The resulting solventsystem was heated to within 1-10° C. of the boiling point for purpose ofpreparing a nearly saturated solution. The nearly saturated solution wasthen cooled to room temperature at a rate not greater than 1-2° C./min.The resulting precipitated material was harvested.

The second process was a fast cooling process (“fast”) whereinnaltrexone base anhydrous (Mallinckrodt) was dissolved in solventforming a solvent system. The resulting solvent system was heated towithin 5-10° C. of the boiling point for purpose of preparing a nearlysaturated solution. The nearly saturated solution was then cooled asrapidly as possible to room temperature. The resulting precipitatedmaterial was harvested.

Table 2 below is a summary of each solvent used, which process wasemployed, and a reference to the Figure which shows the results of eachof the three analytical methods performed.

3. X-Ray Powder Diffraction

Most of the various crystalline forms of naltrexone were analyzed usingX-ray Powder Diffraction. X-ray powder diffraction (XRPD) patterns wereobtained using a Rigaku MiniFlex powder diffraction system, equippedwith a horizontal goniometer in the θ/2-θ mode. The x-ray source wasnickel-filtered K-α emission of copper (1.54056 Å). Samples were packedinto an aluminum holder using a back-fill procedure, and were scannedover the range of 50 to 6 degrees 2-θ, at a scan rate of 0.5 degrees2-0/min. Calibration of each powder pattern was effected using thecharacteristic scattering peaks of aluminum at 44.738 and 38.472 degrees2-θ and these peaks are seen in the pattern. Other XRPDs were analyzedusing a Bruker D8 Advance XRD or a SCINTAC X-ray diffractometer (model#XDS 2000), using 0.02°/step with a 1 second interval. Samples werescanned over the range of 2 to 40 degrees 2-θ at a scan rate of 1 degree2-0/min.

XRPD powder patterns of the various naltrexone precipitated materialsobtained by the slow and fast cooling from a variety of solvent systemsare shown herein in the Figures. The naltrexone forms of the inventionare not limited to those made in accordance with the methods describedherein.

4. Melting/Decomposition Temperature

The temperatures of melting and/or decomposition of naltrexonecrystalline forms were determined using differential scanningcalorimetry (DSC). Most DSC measurements, were obtained on a TAInstruments 2910 thermal analysis system. Samples of approximately 1-2mg were accurately weighed into an aluminum DSC pan, and covered with analuminum lid that was crimped in place. The samples were then heatedover the range of 25-240° C., at a heating rate of 10° C./min.

TABLE 2 Slow Cooling Process Fast Cooling Process Solvent XRPD DSCIR-ATR XRPD DSC IR-ATR Acetonitrile FIG. 1a FIG. 13a FIG. 25a FIG. 1bFIG. 13b FIG. 25b Dimethyl FIG. 2a FIG. 14a FIG. 26a FIG. 2b FIG. 14bFIG. 26b formamide Water ///// ///// ///// FIG. 3 FIG. 15 FIG. 27Methanol FIG. 4a FIG. 16a FIG. 28a FIG. 4b FIG. 16b FIG. 28b EthanolFIG. 5a FIG. 17a FIG. 29a FIG. 5b FIG. 17b FIG. 29b Benzyl alcohol ////////// ///// FIG. 6 FIG. 18 FIG. 30 Dichloromethane FIG. 7a FIG. 19a FIG.31a FIG. 7b FIG. 19b FIG. 31b Acetone FIG. 8a FIG. 20a FIG. 32a FIG. 8bFIG. 20b FIG. 32b Ethyl acetate FIG. 9a FIG. 21a FIG. 33a FIG. 9b FIG.21b FIG. 33b Methyl ethyl FIG. 10a FIG. 22a FIG. 34a FIG. 10b FIG. 22bFIG. 34b ketone Toluene FIG. 11a FIG. 23a FIG. 35a FIG. 11b FIG. 23bFIG. 35b Hexane FIG. 12a FIG. 24a FIG. 36a FIG. 12b FIG. 24b FIG. 36b///// = not available

Melting/decomposition temperature ranges were defined from theextrapolated onset to the maximum of the melting/decompositionendotherm.

Other DSC measurements were obtained by TA Instruments Q 1000 DSC usinghermetic pans and a DSC ramp method using a heating rate of 10° C./min.or 50° C./min. from 0° C. to 200° C. Those skilled in the art willrecognize other appropriate means of measuring DSC.

DSC thermograms of the various naltrexone materials obtained by slow andfast cooling from a variety of solvent systems are shown in the Figures.

5. Infrared Absorption Spectroscopy

The solid-state infrared (IR) spectrum of the analyte was obtained usinga Buck Scientific model M-500 infrared spectrometer, operating in thesingle beam mode, and using the attenuated total reflectance (ATR)detection mode. The sample was clamped against the ZnSe crystal singlereflection horizontal ATR sampling accessory, sold under the tradenameMIRacle™ by Pike Technologies.

IR-ATR spectra of the various Naltrexone products obtained by slow andfast cooling from a variety of solvent systems are shown in the Figures.

Naltrexone Ethanolate

In particular, the Applicants prepared a polymorphic form of naltrexoneethanolate which is characterized by an X-ray powder diffraction with acharacterizing peak at about 9° (2θ). This peak appears irrespective ofwhich of the two processes for preparing were employed.

The resulting analysis showed that the polymorphic form of naltrexonecan be characterized by the X-ray powder diffraction pattern of FIG. 5A.The polymorphic form can be further characterized by the DSC pattern ofFIG. 17A and/or the IR-ATR of FIG. 29A.

This polymorphic form of naltrexone can be characterized by the X-raypowder diffraction pattern of FIG. 5B. The polymorphic form can befurther characterized by the DSC pattern of FIG. 17B and/or the IR-ATRof FIG. 29B.

A polymorphic form of naltrexone ethanolate can also be characterized byFIG. 46. A purified naltrexone ethanolate according to the invention canbe prepared in the substantial absence of one or more polymorphic formsof naltrexone selected from the group consisting of, for example,naltrexone benzyl alcohol solvate, naltrexone monohydrate, and anhydrousnaltrexone. As used herein, the “substantial absence” is intended tomean having no or negligible (including detectable) amounts of theidentified substance, as can be arrived at by processes intending toavoid the formation of the identified substance or by processes intendedto remove the identified substance.

Further, a polymorphic form according to the invention can be preparedwherein the form is in the complete absence of naltrexone benzyl alcoholsolvate, as can be arrived at by employing a process which avoids theuse of benzyl alcohol as or in the solvent system. In anotherembodiment, the polymorphic form is present with naltrexone benzylalcohol solvate, and in amount of at least about 88% or less than about65% by weight of total crystalline naltrexone or, alternatively, is notpresent in an amount of about 67.0%, 76.3 or 85.7% by weight of totalcrystalline naltrexone.

An ethanolate form of naltrexone characterized by the XRPD in FIG. 5A,5B or 46 are examples of a form in the absence of naltrexone benzylalcohol solvate.

Of particular interest to those skilled in the art is a polymorphic formof the invention wherein the form is substantially pure.

Anhydrous Form

Other forms of the invention are contemplated. For example, an anhydrouspolymorphic form of naltrexone was prepared which form can becharacterized by an X-ray powder diffraction with a characterizing peakat about 8° (2θ).

For example, the polymorphic form of naltrexone can be characterized bythe X-ray powder diffraction pattern of FIG. 1A. Additionally, thispolymorphic form can be further characterized by the DSC pattern of FIG.13A. Still further, this polymorphic form can be characterized by theIR-ATR of FIG. 25A.

Such a polymorphic form of naltrexone can be characterized by the X-raypowder diffraction pattern of FIG. 1B. Still further, the polymorphicform can be further characterized by the DSC pattern of FIG. 13B.Additionally, this polymorphic form can be further characterized by theIR-ATR of FIG. 25B.

Alternatively or additionally, the polymorphic form can be characterizedby the XRPD of FIG. 43.

Monohydrate

Applicants also prepared a monohydrate form of naltrexone formed byusing water as the solvent. This polymorphic form of naltrexone ischaracterized by an X-ray powder diffraction with a characterizing peakat about 7° (2θ). This polymorphic form of naltrexone can becharacterized by the X-ray powder diffraction pattern of FIGS. 3 and 44.Further, the polymorphic form at about 7 can be characterized by the DSCpattern of FIG. 15. Additionally, the polymorphic form can be furthercharacterized by the IR-ATR of FIG. 27.

Benzyl Alcohol Solvate

Applicants have prepared another polymorphic form of naltrexone whichcan be characterized by an X-ray powder diffraction with acharacterizing peak at about 5-6° (2θ). Additionally, a polymorphic formof naltrexone can be characterized by the X-ray powder diffractionpattern of FIGS. 6 and 45. Still further, the polymorphic form can becharacterized by the DSC pattern of FIG. 18. Also, a polymorphic formcan be characterized by the IR-ATR of FIG. 30.

Further, a polymorphic form according to the invention can be preparedwherein the form is in the complete absence of naltrexone ethanolate, ascan be arrived at by employing a process which avoids the use of ethanolas or in the solvent system. In another embodiment, the polymorphic formis present with naltrexone ethanolate, and in amount of at least about35% or less than about 13% by weight of total crystalline naltrexone or,alternatively, is not present in an amount of about 33.0%, 23.7 or 14.3%by weight of total crystalline naltrexone.

Other polymorphs, including the solvates specifically described hereinand combinations thereof, are a part of the invention.

Amorphous Naltrexone

Applicants have also prepared an amorphous form of naltrexone which canbe characterized by the DSC pattern of FIG. 42. Amorphous naltrexoneform was prepared by leaving NTX base in 180-190° C. oven forapproximately 10 minutes. After being melted, it was taken out to coolat room temperature. It was then broken up into small pieces using aspatula and ground into fine powders using mortar and pestle. The X-raypowder diffraction pattern confirmed that the powder was amorphous.

Methods of Making an Isolated and/or Substantially Pure Form or Mixtureof Forms of Naltrexone

The forms can be prepared by a method comprising:

(i) mixing a naltrexone, such as a naltrexone base anhydrous or a salt,such as hydrochloride, with a solvent or solvent system containing oneor more organic or aqueous solvents, such as acetonitrile, dimethylformamide, water, methanol, ethanol, benzyl alcohol, dichloromethane,acetone, ethyl acetate, methyl ethyl ketone, toluene and hexane; (ii)heating the solvent or solvent system to within about 1-10° C. of theboiling point to prepare nearly saturated solutions; (iii) slowlycooling the resulting nearly saturated solutions to room temperature,such as at a rate not greater than 1-2° C./min, thereby formingprecipitated materials; and (iv) harvesting the precipitated materials.This method is also referred to herein as the slow process or coolingmethod.

Examples of materials prepared by this method can be characterized bythe X-ray powder diffraction pattern selected from the group consistingof FIGS. 1A, 2A, 4A, 5A, 7A, 8A, 9A, 10A, 11A, and 12A.

Still further, precipitated materials prepared by this method can becharacterized by the DSC pattern selected from the group consisting ofFIGS. 13A, 14A, 16A, 17A, 19A, 20A, 21A, 22A, 23A and 24A. Additionally,the precipitated materials can be characterized by the IR-ATR selectedfrom the group consisting of FIGS. 25A, 26A, 28A, 29A, 31A, 32A, 33A,34A, 35A, and 36A.

Alternatively, Applicants prepared the polymorphs of the instantinvention by the method comprising: (i) mixing a naltrexone baseanhydrous with a solvent selected from the group consisting ofacetonitrile, dimethyl formamide, water, methanol, ethanol, benzylalcohol, dichloromethane, acetone, ethyl acetate, methyl ethyl ketone,toluene and hexane; (ii) heating the solvent or solvent system to withinabout 5-10° C. of the boiling point to prepare nearly saturatedsolutions; (iii) quickly cooling the resulting nearly saturatedsolutions, such as rapidly as possible, to about room temperature, orless, thereby forming precipitated materials; and (iv) harvesting theprecipitated materials. This is also referred to herein as the fastprocess or cooling method.

Material prepared by the fast method can be characterized by the X-raypowder diffraction pattern selected from the group consisting of FIGS.1B, 2B, 3, 4B, 5B, 6, 7B, 8B, 9B, 10B, 11B, and 12B. Further,precipitated materials prepared by this method can be characterized bythe DSC pattern selected from the group consisting of FIGS. 13B, 14B,15, 16B, 17B, 18, 19B, 20B, 21B, 22B, 23B and 24B. Additionally, theycan be characterized by the IR-ATR selected from the group consisting ofFIGS. 25B, 26B, 27, 28B, 29B, 30, 31B, 32B, 33B, 34B, 35B, and 36B.

In one embodiment, the novel forms can be manufactured during theprocess for producing the formulation, such as the specific process forformulating the extended release formulation, referred to herein asformulation A, as described below in the exemplification. In yet anotherembodiment, the invention excludes the extended release formulation,formulation A, described below in the exemplification.

Mixtures of Polymorphic Forms

Applicants have discovered that compositions comprising mixtures of twoor more forms and/or mixtures of crystalline and non-crystalline drugpossess particular advantages in extended release formulations. Thus,the invention also relates to mixtures of such naltrexone products.

In one aspect of the invention, the naltrexone comprises a mixture ofcrystalline and non-crystalline forms. For example, the % crystallinityof the naltrexone can be at least about 10%, preferably at least about20% (by weight) of the total naltrexone, preferably in an amount of atleast about 30%, at least about 40%, at least about 50%, at least about60% (by weight) of the total naltrexone. In one embodiment the %crystallinity of naltrexone is present in an amount between about 10%and 70%, preferably between about 30% and 50% (by weight), of the totalnaltrexone. In another embodiment, the % crystallinity is not 41%,34.3%, or 35.2% of total naltrexone.

The crystalline naltrexone present in such compositions can be anycrystalline form of naltrexone. Preferably the crystalline form includesnaltrexone ethanolate, more preferably naltrexone ethanolate clathrate.The naltrexone ethanolate is preferably present in the crystalline formin an amount of at least about 40% by weight, more preferably in anamount of at least about 50% by weight, more preferably in an amount ofabout 60% by weight.

Non-crystalline naltrexone can be in the form of amorphous and/ordissolved naltrexone relative to the composition or composition matrix.By amorphous (or free amorphous) naltrexone is meant that the amorphousform exists as a separate phase, such as when present in the matrix. Bydissolved naltrexone is meant drug and matrix exist as a single phase.An example of a dissolved naltrexone includes a naltrexone present in apolymeric extended release formulation wherein the naltrexone isdissolved in polymeric matrix. Such an extended release device includesthat described in the exemplification below.

Thus, in one aspect of the invention, the non-crystalline naltrexone inthe naltrexone composition can be from 0-100% by weight dissolved,preferably at least about 20% is dissolved, more preferably at leastabout 50% is dissolved, more preferably at least about 80% is dissolved.In one embodiment, substantially all of the non-crystalline form isdissolved naltrexone.

The inventions also include mixtures of the forms described herein.Thus, the inventions include, for example, naltrexone ethanolate (suchas, naltrexone ethanolate clathrate) alone or in combination with one ormore of the other forms described herein (in the presence, absence orsubstantial absence of non-crystalline (amorphous and/or dissolved)naltrexone). Such combinations can include compositions that havebetween 0 and 100% by weight of any particular form. The compositionpreferably includes naltrexone ethanolate. Preferred amounts ofnaltrexone ethanolate include at least about 10% by weight of totalcrystalline product, preferably at least about 20%, at least about 30%,at least about 40%, at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, or at least about 90% by weight of totalcrystallinity. In one preferred embodiment, the naltrexone ethanolate ispresent in the amount of about 60%. In another embodiment, thenaltrexone ethanolate is absent in the amount of about 60%. Thepercentages represent the fraction of crystallinity as determined byrelative peak intensity of characterizing peaks.

In yet another aspect, compositions of the invention are preparedwherein the crystalline naltrexone is in the substantial absence of apolymorphic form of naltrexone selected from the group consisting of:naltrexone benzyl alcohol solvate, naltrexone monohydrate, and anhydrousnaltrexone. Such compositions preferably possess naltrexone ethanolate,such as naltrexone ethanolate clathrate, in the preferred amountsdescribed above.

A preferred mixture includes about 50-70% naltrexone ethanolate and thebalance naltrexone benzyl alcohol solvate. Another mixture includesabout 10-15% of naltrexone monohydrate; about 10-15% naltrexoneanhydrous; about 10-15% naltrexone benzyl alcohol solvate; and thebalance of the composition is naltrexone ethanolate. Of course, theclaimed invention may include other mixtures of naltrexone forms aswell, including mixtures characterized by two or three of the aboveforms, substituting one or more other forms for one or more of theabove, (including, but not limited to, one or more of the other formsdescribed herein), modifying the amounts of one or more of the forms,adding an additional form, etc.

Utility

The present invention provides a method for the treatment of a patientafflicted with addictive diseases or central nervous system disorderswherein such disease states may be treated by the administration of aneffective amount of naltrexone of the present invention to a patient inneed thereof.

Thus, where the composition is being administered to treat addictivebehavior, a therapeutically effective amount of naltrexone is,preferably, an amount effective in controlling or reducing the addictivebehavior. The term “controlling” is intended to refer to all processeswherein there may be a slowing, interrupting, arresting, or stopping ofthe addictive or other behavior characteristic of the disease and doesnot necessarily indicate a total elimination of all disease symptoms.

The term “therapeutically effective amount” is further meant to definean amount resulting in the improvement of any parameters or clinicalsymptoms. The actual dose may vary with each patient.

As used herein, the term “subject” or “patient” refers to a warm bloodedanimal, including but not limited to humans, such as a mammal which isafflicted with a particular disease state.

A therapeutically effective amount of the compound used in the treatmentdescribed herein can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining the therapeutically effective dose, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

Preferred amounts and modes of administration are able to be determinedby one skilled in the art. One skilled in the art of preparingformulations can readily select the proper form and mode ofadministration depending upon the particular characteristics of thecompound selected, the disease state to be treated, the stage of thedisease, and other relevant circumstances using formulation technologyknown in the art, described for example in Remington's PharmaceuticalSciences, latest edition, Mack Publishing Co.

Pharmaceutical compositions can be manufactured utilizing techniquesknown in the art. Typically the therapeutically effective amount of thecompound will be admixed with a pharmaceutically acceptable carrier.

The compounds or compositions of the present invention may beadministered by a variety of routes, for example, by enteral, oral,buccal, rectal, vaginal, dermal, nasal, bronchial, tracheal, pulmonary,parenteral, subcutaneous, intravenous, intramuscular, or intraperitonealroute, by injection, ingestion, or inhalation, for example.

A particularly preferred route of administration includes sustainedrelease formulations, extended release formulations, or long actingformulations, that permit delivery, such as substantially continuousdelivery of drug over an extended period of time, such as greater thanone, two, three, four or more weeks. A four week release is preferred.

For oral administration, the compounds can be formulated, for example,in a solid, such as capsules, pills, tablets, lozenges, melts, powders,or in a form for mixing into a solution, suspension or emulsion.

In another embodiment, the compounds of this invention can be tablettedwith conventional tablet bases such as lactose, sucrose, and cornstarchin combination with binders, such as acacia, cornstarch, or gelatin,disintegrating agents such as potato starch or alginic acid, and alubricant such as stearic acid or magnesium stearate. Liquidpreparations are prepared by dissolving the active ingredient in anaqueous or non-aqueous pharmaceutically acceptable solvent which mayalso contain suspending agents, sweetening agents, flavoring agents, andpreservative agents as are known in the art.

For parenteral administration the compounds may be dissolved in aphysiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Illustrative of suitablepharmaceutical carriers include water, saline, dextrose solutions,fructose solutions, ethanol, or oils of animal, vegetative, or syntheticorigin. The pharmaceutical carrier may also contain preservatives, andbuffers as are known in the art.

The compounds of this invention can also be administered topically. Thiscan be accomplished by simply preparing a solution of the compound to beadministered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or withoutother excipients. Preferably topical administration will be accomplishedusing a patch either of the reservoir and porous membrane type or of asolid matrix variety.

For surgical implantation, the active ingredients may be combined withany of the well-known biodegradable and bioerodible carriers, such aspolylactides and poly-lactide-co-glycolides and collagen formulations.Such materials may be in the form of solid implants, sponges, and thelike. In any event, for local use of the materials, the activeingredients usually be present in the carrier or excipient in a weightratio of from about 1:1000 to 1:20,000, but are not limited to ratioswithin this range.

Preferably, the compounds are in an extended release formulation.Extended (also referred to as sustained or controlled release)preparations may be achieved through the use of polymers (preferablypoly-lactide or poly-lactide-co-glycolide polymers) to entrap orencapsulate the naltrexone described herein. Extended releaseformulations can be made by spray drying polymer-drug mixtures,emulsion-based technologies, coacervation based technologies, filmcasting, extrusion based technologies and other processes to manufacturepolymer-drug microparticles possessing an extended release profile.Examples of suitable extended release technologies that can be used toincorporate the novel naltrexone forms described herein include, withoutlimitation, the MEDISORB® technology, as described in, for example, U.S.Pat. No. 6,264,987 to Wright, U.S. Pat. No. 5,654,008 and/or U.S. Pat.No. 5,792,477, for example; the PROLEASE® technology, as described, forexample in U.S. Pat. No. 6,358,443 to Herbert; the technologiesdescribed by Southern Research Institute, as described for example inU.S. Pat. No. 6,306,425; and “Method of Preparing Sustained ReleaseMicroparticles,” U.S. Application No. 60/441,946, filed Jan. 23, 2003,and the technologies described by Alza Corp., including the ALZAMER®Depot injection technology. The contents of these patents areincorporated herein by reference in their entirety.

In a preferred embodiment, the extended release formulation deliverstherapeutically beneficial amounts of naltrexone to the patient for aperiod of at least one week, preferably at least about two weeks, morepreferably at least about 3 or about 4 or more weeks.

In one preferred embodiment, the naltrexone is present in the extendedrelease device or formulation in an amount of at least about 5% byweight, preferably at least about 10% by weight, more preferably atleast about 30% by weight of the total weight of the device, orformulation. In one embodiment, the theoretical drug load is not 35% (oractual drug load of 40%, 45.8% or 26.1% load) by weight of the totalsustained release device. However, in a preferred embodiment, thetheoretical drug load is 35% total naltrexone.

It has been discovered that controlling the crystallinity of the totalamount of naltrexone has a substantial impact upon the duration ofrelease. For example, a composition containing PLGA microspheres, asdescribed herein, characterized by total % naltrexone crystallinitybetween about 9-12% in a PLGA microsphere possesses a superior releaseprofile of about 4 weeks. Lowering the % crystallinity can quicken therelease. Thus, a composition containing PLGA microspheres, as describedherein, characterized by total % naltrexone crystallinity of betweenabout 4-9% in a PLGA microsphere possesses a superior release profile ofless than 4 weeks, e.g. about 2 weeks. Likewise, a compositioncontaining PLGA microspheres, as described herein, characterized bytotal % naltrexone crystallinity of about 12% or more in a PLGAmicrosphere possesses a superior release profile of at least 4 weeks,e.g. about 8 weeks. Such a substantial impact upon the duration ofrelease, based on the % crystallinity was unexpected.

Alternatively, instead of incorporating naltrexone into polymericparticles, it is possible to entrap these materials in microparticlesprepared. For example, coacervation techniques, interfacialpolymerization (for example, hydroxymethylcellulose orgelatine-microcapsules and poly-(methylmethacrylate) microcapsules,respectively), colloidal drug delivery systems (for example, liposomes,albumin, microparticles, microemulsions, nanoparticles, andnanocapsules), or macroemulsion systems can be used.

When the composition is to be used as an injectable material, includingbut not limited to needle-less injection, it can be formulated into aconventional injectable carrier. Suitable carriers include biocompatibleand pharmaceutically acceptable solutions.

Method for Manufacturing Extended Release Devices

The invention includes a preferred method for manufacturing extendedrelease devices, wherein the resulting device contains preferredmixtures of the described polymorphic forms.

Polymer solution can be formed by dissolving apoly(lactide)-co-glycolide polymer, such as a 75:25 DL PLGA(poly(lactide)-co-glycolide) in a polymer solvent, such as ethyl acetate(EtAc), to form a solution. Preferred PLGA polymers are high molecularweight polymers, such as polymers possessing a molecular weight of atleast about 100,000 daltons. A naltrexone solution can be formed bydissolving naltrexone base in a suitable solvent, such as one of thesolvents described above, including benzyl alcohol (BA), to form asolution. The polymer solution and the naltrexone solution arepreferably mixed together to form a drug/polymer solution that will bethe “organic” or “oil” phase of the emulsion.

The “aqueous” or “continuous” phase of the emulsion (emulsifyingsolution) is prepared. The aqueous phase preferably contains poly(vinylalcohol) (PVA) and polymer solvent, such as EtAc. The organic phase andthe aqueous phase can be conveniently combined in a first static mixerto form an oil-in-water emulsion.

In an optional partial extraction step, the emulsion flows out of thefirst static mixer and into a second static mixer where the emulsion canbe combined with a primary extraction solution which enters the secondstatic mixer. The primary extraction solution (such as can be formed byan EtAc aqueous solution) can initiate solvent extraction from themicrodroplets of the emulsion during the partial primary extraction stepin the second static mixer.

The outflow of the first or second static mixer can flow into anextraction vessel containing primary extraction solution. The solvents(BA and EtAc) are substantially extracted from the organic phase of theemulsion in this primary solvent extraction step, resulting in nascentmicroparticles comprised mainly of polymer and drug. The primary solventextraction step lasts for approximately six hours.

The microparticles can be collected, and vacuum dried, optionally with anitrogen bleed using a customized vibratory sieve. After collection andprior to drying, the microparticles are rinsed with a 25% ethanolsolution that removes the emulsifying agent (PVA), and enhances yield byaiding in the transfer of the microparticles to the cold dryer. Thisstep is conducted, preferably at cold temperatures, until the desiredlevel of dryness is achieved. As can be seen in the examples below, thedegree of dryness (as measured, for example, by a humidity probe)impacts the degree of crystallinity achieved in the final product. Forexample, it can be advantageous to select a drying time of at leastabout 8, 16, 24 or 40 hours of drying. For example, it can beadvantageous to select a drying time of at least about 8, 16, 24 or 40hours where drying is 40%, 70%, 95% or 100% complete respectively.Drying is considered complete when the absolute humidity of the effluentgas reaches approximately 0 g/m³.

The microparticles can then be resuspended in a second extractionsolution. The second solution can contain the solvent desired to formthe polymorphic form, such as ethanol. For example, a solutioncomprising at least about 10% ethanol by volume, preferably at leastabout 20% ethanol by volume can be used. This can be conveniently calledthe reslurry and secondary solvent extraction steps. The solvent, suchas ethanol, can facilitate further extraction of BA and EtAc. Further,the crystallinity of the drug increases during the step. The secondarysolvent extraction step is carried out in an extraction vessel forapproximately two, three, four or more hours. This step can beconveniently completed at room temperature. However, other temperaturescan be selected as well. In the collection/final dry step, themicroparticles are collected, and vacuum dried with a nitrogen bleedusing a customized vibratory sieve.

In the final harvest step, the microparticles can be transferred into asterile container and stored, for example, in a freezer at −20° C.,until filling into vials. Preferably, the stored microparticles aresieved through a 150 micron screen to remove any oversized materialprior to filling into vials.

EXEMPLIFICATION Example 1

The following solvates were made as described below. Thereafter theresulting precipitated material was analyzed using the analyticaltechniques described above, that is, X-ray powder diffraction,differential scanning calorimetry and infrared attenuated totalreflectance (IR-ATR) detection mode.

Acetonitrile [XRPD=FIG. 1; DSC=FIG. 13; IR-ATR=FIG. 25]

Crystallization out of this solvent yields an anhydrous form. Somevariability in XRPD powder pattern is noted for substances obtained byfast and slow cooling, but the characteristic peaks are noted at thesame scattering angles. This phase is characterized by a DSC meltingtransition having a temperature maximum of 175° C.

Dimethyl formamide [XRPD=FIG. 2; DSC=FIG. 14; IR-ATR=FIG. 26]

Crystallization out of this solvent yields the DMF solvate, which ischaracterized by a DSC desolvation transition having a temperaturemaximum of 113° C. The XRPD powder patterns of substances obtained byfast and slow cooling differs, and the fast cooling sample containsadditional peaks not observed in the powder pattern of the slow coolingsample. The desolvation of the material obtained by slow cooling yieldedan amorphous material that did not recrystallize to a form capable ofexhibiting a melting endotherm. This property is most likelycharacteristic of the DMF solvate. The fast cooling sample exhibited asecond endothermic transition, having a DSC melting transition maximumat 167° C., which is most likely due to the presence of the second phasein the fast cooling sample.

Water [XRPD=FIG. 3; DSC=FIG. 15; IR-ATR=FIG. 27]

Crystallization out of this solvent yields a hydrate, which is largelycharacterized by a DSC desolvation transition having a temperaturemaximum of 99° C. The dehydration of this hydrate yields detectablerecrystallization phenomena, forming an anhydrous form having a DSCmelting transition maximum at 160° C. During its melting transition,this form undergoes another crystallization transition, yielding theanhydrous form characterized by a DSC melting transition that has atemperature maximum of 175° C.

Methanol [XRPD=FIG. 4; DSC=FIG. 16; IR-ATR=FIG. 28]

Crystallization out of this solvent yields a methanol solvate. The XRPDpowder patterns of substances obtained by fast and slow cooling differ,with the slow cooling sample containing additional peaks not observed inthe powder pattern of the fast cooling sample. Interestingly, thisdifference does not carry over into the DSC of the two materials. Bothsamples were characterized by a DSC desolvation transition having atemperature maximum of 108° C., followed by well-definedmelting/crystallization/melting phenomena at temperatures of 160° C.,162° C., and 175° C., respectively.

Ethanol [XRPD=FIG. 5; DSC=FIG. 17; IR-ATR=FIG. 29]

Crystallization out of this solvent yields an ethanol solvate. The XRPDpowder patterns of substances obtained by fast and slow cooling differsubstantially, with the fast cooling sample containing additional peaksnot observed in the powder pattern of the slow cooling sample. The DSCthermogram of the slow cooling sample is characterized by a desolvationtransition having a temperature maximum of 120° C., eventually followedby a melting/crystallization/melting sequence at temperatures of 160°C., 161° C., and 175° C., respectively. The DSC of the fast coolingsample contains a prominent desolvation endotherm having a temperaturemaximum of 92° C., which is most likely due to the presence of waterhaving condensed in the sample during its crystallization. Thetemperature of this endotherm differs from that of the authentichydrate, and may represent the formation of a mixed hydrate/ethanolpolymorph.

Benzyl Alcohol [XRPD=FIG. 6; DSC=FIG. 18; IR-ATR=FIG. 30]

Crystallization out of this solvent yields a benzyl alcohol solvate.This polymorph is largely characterized by a DSC desolvation transitionhaving a temperature maximum of 124° C. The dehydration of this hydrateyields weak, but detectable, recrystallization phenomena, forminganhydrous forms having DSC melting transition maxima at 153° C. and 160°C.

Dichloromethane [XRPD=FIG. 7; DSC=FIG. 19; IR-ATR=FIG. 31]

Crystallization out of this solvent yields a dichloromethane solvate.The XRPD powder patterns of substances obtained by fast and slow coolingappear to be completely different, although the powder pattern of thefast cooling sample strongly resembles the powder patterns of the twoanhydrous materials crystallized out of acetonitrile. The DSC thermogramof the slow cooling sample is largely characterized by a meltingtransition having a peak maximum at 176° C. Comparison of all of thedata indicates that this anhydrous form is the same anhydrous form ashad been crystallized out of acetonitrile. The DSC of the slow coolingsample contains a prominent desolvation endotherm having a temperaturemaximum of 90° C., which is most likely due to the presence of waterhaving condensed in the sample during its crystallization. Thetemperature of this endotherm differs from that of the authentichydrate, and may represent the formation of a mixedhydrate/dichloromethane polymorph. The apparent co-crystallization ofthe hydrate represents the origin of the differences noted in the twosets of powder patterns for materials crystallized out ofdichloromethane.

Acetone [XRPD=FIG. 8; DSC=FIG. 20; IR-ATR=FIG. 32]

Crystallization out of this solvent yields an acetone solvate. The XRPDpowder patterns of substances obtained by fast and slow cooling exhibitdifferences in relative intensities (probably associated withpreferential orientation), but the overall pattern of scattering anglesis fairly comparable between the two. The DSC thermograms of the twosamples are also quite similar, being characterized by a desolvationtransition having a temperature maximum of 138° C., and eventuallyfollowed by a melting endotherm at a temperature 176° C. Prior to thelarge melting endotherm (temperature around 160° C.), there is a weakmelt/recrystallization endotherm as well.

Ethyl Acetate [XRPD=FIG. 9; DSC=FIG. 21; IR-ATR=FIG. 33]

Crystallization out of this solvent yields an ethyl acetate solvate. TheXRPD powder patterns of substances obtained by fast and slow coolingdiffer substantially. The DSC thermogram of both polymorphs ischaracterized by a desolvation transition having a temperature maximumof 123° C., eventually followed by a melting/crystallization/meltingsequence at temperatures of 161° C., 162° C., and 176° C., respectively.The DSC of the fast cooling sample also contains a prominent desolvationendotherm having a temperature maximum of 91° C., which is most likelydue to the presence of water having condensed in the sample during itscrystallization. The temperature of this endotherm differs from that ofthe authentic hydrate, and may represent the formation of a mixedhydrate/ethyl acetate polymorph.

Methyl Ethyl Ketone [XRPD=FIG. 10; DSC=FIG. 22; IR-ATR=FIG. 34]

Crystallization out of this solvent yields an anhydrous form. The XRPDpowder patterns of substances obtained by fast and slow cooling arequite similar, and each strongly resembles the powder patterns of theanhydrous materials crystallized out of acetonitrile. The DSC thermogramof the slow cooling sample contains an endothermic transition at verylow temperatures, but is still dominated by the melting transitionhaving a peak maximum at 176° C. The DSC of the fast cooling sampleconsists essentially of only the melting endotherm (maximum at 176° C.).

Toluene [XRPD=FIG. 11; DSC=FIG. 23; IR-ATR=FIG. 35]

Crystallization out of this solvent yields a toluene solvate. The XRPDpowder patterns of substances obtained by fast and slow cooling exhibita significant number of qualitative differences that are probablyrelated to preferential orientation. The DSC thermograms of the twosamples are also fairly similar, being characterized by a desolvationtransition having a temperature maximum of 138° C., and eventuallyfollowed by a melting endotherm at a temperature of 176° C. Prior to thelarge melting endotherm (temperature around 160° C.), there is a weakmelt/recrystallization endotherm as well.

Hexane [XRPD=FIG. 12; DSC=FIG. 24; IR-ATR=FIG. 36]

Crystallization out of this solvent yields a hexane solvate. The XRPDpowder patterns of substances obtained by fast and slow cooling stronglyresemble each other, and only differ in some of the relativeintensities. The DSC thermogram of the sample obtained through the useof fast cooling is characterized by a desolvation transition having atemperature maximum of 114° C., and which is eventually followed by amelting/crystallization/melting sequence at temperatures of 153° C.,158° C., and 174° C., respectively. The DSC of the slow cooling samplealso contains a prominent desolvation endotherm having a temperaturemaximum of 91° C., which is most likely due to the presence of waterhaving condensed in the sample during its crystallization. Thetemperature of this endotherm differs from that of the authentichydrate, and may represent the formation of a mixed hydrate/ethylacetate polymorph.

Example 2 Preparation of Naltrexone-Containing MicroparticlesFormulation A

The naltrexone base microparticles were produced using a co-solventextraction process. The theoretical batch size was 15 to 20 grams. Thepolymer (MEDISORB® 7525 DL polymer, MEDISORB® 8515 DL polymer andMEDISORB® 6536 DL polymer, all available from Alkermes, Inc., Blue Ash,Ohio) was dissolved in ethyl acetate to produce a 16.7% w/w polymersolution. The naltrexone base anhydrous was dissolved in benzyl alcoholto produce a 30.0% w/w solution. In various batches, the amount of drugand polymer used was varied to produce microparticles with differenttheoretical drug loading ranging from 30%-75%. The ambient polymer anddrug solutions were mixed together until a single homogeneous solution(organic phase) was produced. The aqueous phase was at ambientconditions and contained 1% w/w polyvinyl alcohol and a saturatingamount of ethyl acetate. These two solutions were pumped via positivedisplacement pumps at a ratio of 3:1 (aqueous:organic) through a ¼″in-line mixer to form an emulsion. The emulsion was transferred to astirring solvent extraction solution consisting of 2.5% w/w of ethylacetate dissolved in distilled water at 5-10° C., at a volume of 0.5 Lof extraction solution per theoretical gram of microparticles. Both thepolymer and drug solvents were extracted into the extraction solutionfrom the emulsion droplets to produce microparticles. The initialextraction process ranged from two to four hours. The microparticleswere collected on a 25 μm sieve and rinsed with a cold (<5° C.) 25% w/wethanol solution. The microparticles were dried cold overnight(approximately 17 hours) using nitrogen. The microparticles were thentransferred to the reslurry solution, which consisted of a vigorouslystirring 25% w/w ethanol solution at 5-10° C. After a short mixing time(five to fifteen minutes), the reslurry solution and the microparticleswere transferred to a stirring 25% w/w ethanol secondary extractionsolution (approximately 25° C. at a volume of 0.2 L of secondaryextraction solution per theoretical gram of microparticles). Themicroparticles stirred for six hours enabling additional solvent removalfrom the microparticles to take place. The microparticles were thencollected on a 25 μm sieve and rinsed with a 25% w/w ethanol solution atambient temperature. These microparticles dried in a hood under ambientconditions overnight (approximately 17 hours), were sieved to removeagglomerated microparticles and then placed into a freezer for storage.

Example 3

A 1 kg batch of naltrexone microspheres were prepared as follows.Polymer solution was formed by dissolving 75:25 DL PLGA(poly(lactide)-co-glycolide) in ethyl acetate (EtAc) to form a solutionof 16.7% polymer and 83.3% EtAc. A naltrexone solution was formed bydissolving naltrexone base in benzyl alcohol (BA) to form a solution of30% naltrexone base anhydrous and 70% BA. The polymer solution and thenaltrexone solution were mixed together to form a drug/polymer solutionthat was the “organic” or “oil” phase of the emulsion.

The “aqueous” or “continuous” phase of the emulsion (emulsifyingsolution) was prepared by dissolving poly(vinyl alcohol) (PVA) and EtAcin water-for-injection (WFI). The organic phase and the aqueous phasewere combined in a first static mixer to form an oil-in-water emulsion.The droplet size of the emulsion was determined by controlling the flowrates of the two phases through the first static mixer.

In a partial primary extraction step, the emulsion flowed out of thefirst static mixer and into a second static mixer where the emulsion wascombined with a Primary extraction solution which enters the secondstatic mixer. The primary extraction solution (2.5% EtAc and 97.5% WFIat approximately 6° C.) initiated solvent extraction from themicrodroplets of the emulsion during the partial primary extraction stepin the second static mixer.

The outflow of the second static mixer (combined flow stream of theemulsion and the primary extraction solution) flowed into an extractionvessel containing primary extraction solution. The solvents (BA andEtAc) were further extracted from the organic phase of the emulsion inthis primary solvent extraction step, resulting in nascentmicroparticles comprised mainly of polymer and drug. The primary solventextraction step lasted for approximately six hours.

The microparticles were collected, and vacuum dried with a nitrogenbleed using a customized vibratory sieve. After collection and prior todrying, the microparticles were rinsed with a 25% ethanol solution thatremoves the emulsifying agent (PVA), and enhances yield by aiding in thetransfer of the microparticles to the dryer.

To further reduce the solvent levels the microparticles were resuspendedin a second extraction solution of 25% ethanol and 75% WFI in thereslurry and secondary solvent extraction steps. The ethanol facilitatedfurther extraction of BA and EtAc. The secondary solvent extraction stepwas carried out in an extraction vessel for approximately four hours. Inthe collection/final dry step, the microparticles were collected, andvacuum dried with a nitrogen bleed using a second customized vibratorysieve.

In the final harvest step, the microparticles were transferred into asterile container and stored in a freezer at −20° C. until filling intovials. Preferably, the stored microparticles were sieved through a 150micron screen to remove any oversized material prior to filling intovials.

Several lots of microspheres prepared by the method above were stored atvarious temperatures for varying periods of time. Table 3 below showsthe percent crystallinity as determined by XRPD of each lot when storedfor up 25 months at frozen, refrigerated and room temperatureconditions. The results for each lot are within the tolerance levels ofthe methodology and demonstrate that the percent crystallinity of eachlot remains stable over time.

TABLE 3 Stability Lots - Percent Crystallinity (XRPD) FrozenRefrigerated Room Temp Lot Interval −10° C. 4-8° C. 25° C. 1 25 months14.2% NA 14.0% 2 24 months 13.7% 13.8% NA 3 20 months 13.1% NA 14.9% 416 months 15.3% NA 13.9% 5 15 months 7.6% NA 8.5% 6 15 months 8.5% NA8.6% 7 10 months 16.0% NA 14.6% 8  3 months 5.4% NA 5.6% NA = notavailable X-ray powder diffraction

Twenty-one lots of naltrexone microparticles were prepared in accordancewith the process described in Example 3 above to produce microparticleshaving a theoretical drug load of 35%. Each of the 21 lots was analyzedby x-ray powder diffraction (XRPD) using a Bruker D8 Advance XRD using0.02°/step with a 1 second interval from 2.5° to 40° 2-theta. Percentcrystallinity was determined by AUC subtraction of the amorphous haloand calculated as a ratio of the crystalline AUC to total AUC. Percentcrystallinity is reported as percent of total microparticle rather thanas percent of drug load. The lots contain approximately 35% drug load.Therefore, 10.5% crystallinity calculates to be 30% of the total drugload.

The x-ray powder patterns obtained for naltrexone anhydrous,monohydrate, benzyl alcohol solvate, and ethanolate polymorph forms wereanalyzed. Table 4 shows the approximate 2-theta angles used to initiallyidentify each form. FIG. 39 contains the x-ray powder pattern for onelot and identifies four forms. These data clearly indicate that the fourforms are present in the microparticles.

TABLE 4 Identifying 2-theta angle for the naltrexone polymorphsPolymorphic form 2-theta angle (approximate) Anhydrous 8° Monohydrate 7°Benzyl alcohol solvate 5.5° or 5.6° and/or 7.3° Ethanolate 8.1° and/or9°

Table 5A displays the percent crystallinity (of total weight of themicroparticles produced by the process) and relative percentdistribution of each of the four polymorphic forms for the 21 lots.These data demonstrate that the relative ratio of the four polymorphicforms is generally consistent, regardless of the total crystallinity.These data further show that greater than about 55% of the naltrexonedrug load is non-crystalline.

TABLE 5A Benzyl Lot Percent Alcohol Number Crystallinity SolvateMonohydrate Anhydrous Ethanolate 1 13.0 6.1 9.4 16.9 67.6 2 7.1 5.6 9.014.9 70.6 3 7.8 7.4 7.4 15.4 69.8 4 16.0 11.8 17.8 14.4 55.9 5 11.8 11.015.8 11.0 62.1 6 8.2 5.6 10.0 19.7 64.7 7 9.0 8.9 10.4 15.6 65.1 8 5.911.8 11.4 13.3 63.6 9 7.3 9.9 16.3 14.7 59.2 10 8.5 7.2 12.4 16.3 64.111 5.7 8.9 12.2 14.1 64.8 12 7.4 10.6 14.1 14.8 60.5 13 3.6 13.1 19.216.2 51.5 14 5.8 15.5 17.9 13.2 53.4 15 6.8 8.0 16.0 19.4 56.6 16 12.07.8 12.6 16.6 63.0 17 11.5 11.8 14.3 15.3 58.6 18 11.2 11.4 16.7 14.357.5 19 15.7 10.3 15.9 14.7 59.1 20 10.4 10.7 13.9 13.4 62.0 21 11.0 9.316.3 16.8 57.6 Mean 9.3 9.7 13.8 15.3 61.3 STD 3.3 2.6 3.3 2.0 5.0 DEV %RSD 35.4 26.6 24.0 13.0 8.2 Min 3.6 5.6 7.4 11.0 51.5 Max 16.0 15.5 19.219.7 70.6

Subsequently, a more comprehensive data analysis was conducted using theBruker D8 Advance XRD and EVA software comparing the 2-theta angles andd-spacing from samples of the 4 polymorphs to the VIVITREX®microspheres. This analysis revealed that the 4 apparent identificationpeaks visually observed were actually 2 pairs of identification peaksfrom 2 polymorphs (benzyl alcohol solvate and ethanolate) and only thesepolymorphs were identifiable in the microspheres. The data for the abovelots as well as additional lots is set forth in Table 5B.

TABLE 5B Benzyl Alcohol Percent Solvate Ethanolate Percent CrystallinityCrystallinity (Percent of (Percent of (Of (Of drug total total ExampleScale microsphere) load) crystallinity) cystallinity) 1 1 kg 13.0 37.114.6 85.4 2 1 kg 7.1 20.3 15.6 84.4 3 1 kg 7.8 22.3 13.7 86.3 4 1 kg16.0 45.7 28.9 71.1 5 1 kg 11.8 33.7 25.4 74.6 6 1 kg 8.2 23.4 13.6 86.47 1 kg 9.0 25.7 20.2 79.8 8 1 kg 5.9 16.9 22.8 77.2 9 1 kg 7.3 20.9 24.275.8 10 1 kg 8.5 24.3 13.2 86.8 11 1 kg 5.7 16.3 22.0 78.0 12 1 kg 7.421.1 22.1 77.9 13 1 kg 3.6 10.3 24.3 75.7 14 1 kg 5.8 16.6 33.4 66.6 151 kg 6.8 19.4 23.7 76.3 16 1 kg 12.0 34.3 19.1 80.9 17 1 kg 11.5 32.925.6 74.4 18 1 kg 11.2 32.0 27.0 73.0 19 1 kg 15.7 44.9 25.6 74.4 20 1kg 10.4 29.7 23.0 77.0 21 1 kg 11.0 31.4 24.9 75.1 22 1 kg 7.6 21.7 17.482.6 23 1 kg 8.1 23.1 20.6 79.4 24 1 kg 5.3 15.1 10.4 89.6 25 1 kg 7.020.0 22.9 77.1 26 1 kg 9.8 28.0 16.9 83.1 27 1 kg 11.2 32.0 26.7 73.3 281 kg 13.0 37.1 17.3 82.7 29 1 kg 13.3 38.0 24.1 75.9 30 1 kg 8.1 23.116.0 84.0 31 1 kg 10.4 29.7 23.4 76.6 32 1 kg 8.4 24.0 21.7 78.3 33 1 kg7.9 22.6 15.8 84.2 34 1 kg 8.8 25.1 26.3 73.7 35 1 kg 13.9 39.7 13.286.8 36 1 kg 6.8 19.4 10.9 89.1 37 1 kg 6.5 18.6 8.2 91.8 38 1 kg 12.936.9 21.1 78.9 39 1 kg 5.0 14.3 17.0 83.0 40 1 kg 7.2 20.6 0.0 100 41 1kg 10.8 30.9 26.1 73.9 42 1 kg 12.9 36.9 32.0 68.0 43 1 kg 5.7 16.3 0.0100.0 44 225 g 17.1 48.9 9.5 90.5 45 225 g 15.2 43.4 12.3 87.7 46 225 g13.2 37.7 14.7 85.3 47 225 g 18.4 52.6 8.0 92.0 48 225 g 13.7 39.1 6.094.0 49 225 g 15.8 45.1 8.2 91.8 50 225 g 12.7 36.3 13.6 86.4 Mean 10.028.7 18.5 81.5 STD DEV 3.6 10.2 7.6 7.6 Min 3.6 10.3 0.0 66.6 Max 18.452.6 33.4 100.0

The process was repeated employing different drying times for the “firstdry”. The percent crystallinity reported for each run is reported in thefollowing table and FIG. 38.

TABLE 6 Effect of Dryness (1^(st) Dry) on Drug Product CrystallinityTime of Dry, % Completeness % Crystallinity of Batch # Hours Of DryingMicroparticle 02-017-076 E1 8 43.7% 3.7 02-017-076 E2 16 76.6% 4.6%02-017-076 E3 24 98.8% 6.4% 02-017-076 E4 40 100% 16.1% Completeness ofdrying is defined as the ratio of the AUC of the effluent gas absolutehumidity over time up to a specified time to the AUC of the absolutehumidity over time up to the final time point (i.e., time at whichabsolute humidity reaches 0 g/m³.

Modifications and variations of the invention will be obvious to thoseskilled in the art from the foregoing detailed description of theinvention. Such modifications and variations are intended to come withinthe scope of the appended claims.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. (canceled)
 2. A polymorphic form of naltrexone hexane solvate whichis characterized by at least one of: (a) the X-ray powder diffractionpattern of FIG. 12A; (b) the differential scanning calorimetrythermogram of FIG. 24A; and (c) the IR-ATR spectrum of FIG. 36A.
 3. Apharmaceutical composition comprising the polymorphic form according toclaim 2 and a pharmaceutically acceptable carrier.
 4. A polymorphic formof naltrexone hexane solvate which is characterized by at least one of:(a) the X-ray powder diffraction pattern of FIG. 12B; (b) thedifferential scanning calorimetry thermogram of FIG. 24B; and (c) theIR-ATR spectrum of FIG. 36B.
 5. A pharmaceutical composition comprisingthe polymorphic form according to claim 4 and a pharmaceuticallyacceptable carrier.